Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone
L.M. Calvi, … , R. Baron, E. Schipani
L.M. Calvi, … , R. Baron, E. Schipani
Published February 1, 2001
Citation Information: J Clin Invest. 2001;107(3):277-286. https://doi.org/10.1172/JCI11296.
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Activated parathyroid hormone/parathyroid hormone–related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone

Abstract

Parathyroid hormone (PTH), an important regulator of calcium homeostasis, targets most of its complex actions in bone to cells of the osteoblast lineage. Furthermore, PTH is known to stimulate osteoclastogenesis indirectly through activation of osteoblastic cells. To assess the role of the PTH/PTH-related protein receptor (PPR) in mediating the diverse actions of PTH on bone in vivo, we generated mice that express, in cells of the osteoblastic lineage, one of the constitutively active receptors described in Jansen’s metaphyseal chondrodysplasia. In these transgenic mice, osteoblastic function was increased in the trabecular and endosteal compartments, whereas it was decreased in the periosteum. In trabecular bone of the transgenic mice, there was an increase in osteoblast precursors, as well as in mature osteoblasts. Osteoblastic expression of the constitutively active PPR induced a dramatic increase in osteoclast number in both trabecular and compact bone in transgenic animals. The net effect of these actions was a substantial increase in trabecular bone volume and a decrease in cortical bone thickness of the long bones. These findings, for the first time to our knowledge, identify the PPR as a crucial mediator of both bone-forming and bone-resorbing actions of PTH, and they underline the complexity and heterogeneity of the osteoblast population and/or their regulatory microenvironment.

Authors

L.M. Calvi, N.A. Sims, J.L. Hunzelman, M.C. Knight, A. Giovannetti, J.M. Saxton, H.M. Kronenberg, R. Baron, E. Schipani

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Figure 5

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Analysis of cortical bone. (a–d) Histologic sections of cortical bone fr...
Analysis of cortical bone. (a–d) Histologic sections of cortical bone from tibial mid-diaphysis of 8-week-old wild-type (a) and CL1 transgenic (b) littermates and 12-week-old wild-type (c) and CL2 transgenic (d) littermates. (e and f) Histomorphometric analysis performed in 12-week-old wild-type (light blue) and CL2 (dark blue) littermates. AP < 0.05, BP < 0.01. Error bars represent the SEM. MAR, mineral apposition rate. (g–r) High-power (×200) light microscopy images of the mid-diaphysis of in situ hybridization with the 35S-labeled alkaline phosphatase (g–j), collagen I (k–n), and osteocalcin (o–r) cRNAs in serial sections of decalcified proximal tibia of 2-week-old wild-type (g, h, k, l, o, p) and CL2 (i, j, m, n, q, r) mice; sections were counterstained with hematoxylin and eosin. Bright-field (g, i, k, m, o, q) and dark-field (h, j, l, n, p, r) views are shown. The arrow indicates the periosteal surface.